OTS Rare Disease N-of-1+ Workshop Briefing Document
This briefing document aims to outline the current state of the art of oligonucleotide therapies for those planning to develop individualized therapies for patients with very rare diseases or mutations. The focus is on approved modalities and tissues for which good delivery of oligonucleotides has been confirmed in humans. We believe development of individualized therapies should build on those approaches.
As the oligonucleotide therapy field is dynamic, this document will be dynamic as well. Initially we had planned a meeting to discuss outstanding issues in spring 2020. Currently due to the COVID-19 pandemic, this is not feasible. However, we still believe that a discussion about this topic is timely. We therefore welcome input and comments from the oligonucleotide therapy field in the comment box. This will initiate an online discussion now, and will help us to update this document as needed and also plan for a stakeholder meeting to discuss outstanding issues with those involved (scientists, regulators, patients and funders) in 2021.
Click Here to Read the Briefing Document
Please leave your comments and feedback to the briefing document in the comment box below or email us at raredisease@oligotherapeutics.org.
Thank you for your input, on behalf of the OTS Rare Disease N-of-1+ task force,
Annemieke Aartsma-Rus
Keith Gagnon
Art Krieg
Jon Watts
Tim Yu
This is a very thorough and useful document. I have a few comments:
1) In the Workflow Schematic 1 Step 2 and section 2.3.A consider adding in vivo Pharmacology Studies, especially in established animal models if available.
2) 2.1.A Consent can be obtained from minor’s parent(s), OR legal guardian, OR legally authorized representative to give permission for the minor to take part in the study.
3) 2.3.B re Safety Screening for IT administered drugs I think it is important to note that non-human primates are more likely to translate to human than rodents.
4) 2.4.B re Pharmacokinetic studies – if these are required then it should be noted that development of the correct assays can require substantial effort and resources.
5) 2.4.B Should there be a comment about preference for using juvenile animals to study safety effects if the intended patients are pediatric?
6) 2.4.C Clinical Safety Issues should note the potential for thrombocytopenia – this is a warning that is present on several ASO labels.
7) 2.4.C Clinical Safety – IT ASO can cause transient hindlimb hyporeflexia, paresis or ataxia when administered in cynomolgus monkeys. The relevance of this to humans is uncertain.
8) section 3 – Assuring fair access is a complicated ethical issue. There should be an effort to establish accepted criteria on how to decide which patients to select for development of N-of-1+ treatment. Thanks for the opportunity to comment.
Thank you very much for your comments, Barry!
Please note that we will update the briefing document regularly and we will implement comment 1 and comment 7 during this update. We will also implement comment 6, and specify that this applies to systemic treatment.
For your comments about safety and pharmacokinetic studies in vivo: the challenge of developing ASO therapies for very small groups of patients (often single individuals) with a progressive disease is that each additional test adds time to the development path during which the entire treatment cohort (i.e. this one individual) will likely irreversably lose functions. As such, we propose to keep the preclinical and safety package as limited as possible and build on experience from similar compounds with similar delivery routes (e.g. milasen and nusinersen), and performing a dose escalation in the patient.
The use of juvenile animals (or not) is something we like to discuss with regulators and the field at large.
Comment 8: we fully agree! This is something we want to discuss during the face to face meeting. The current document gives some guidance on who best to select, but this is only the start.
Thanks again for your comments and everyone feel free to comment to the comments or the reply – we hope to get a virtual discussion going while face to face discussions are not possible.
Very thoughtful comments, Barry, Thanks! As Annemieke mentioned, we’ll update the document, trying to highlight the key issues that balance speed and safety so that we also can maximize access. Definitely need to have deeper discussions on all of the issues involved in this with all stakeholders, including bioethicists, patients, and patient advocacy groups.
It’s an exciting time in our field as the technologies that our community has developed are finding so many new opportunities to save lives – how do we safely maximize this? Lot’s more work and discussion needed!
I wonder whether AMCs/investigators or CROs who make the drug for the n-of-1 trial have to worry about IP issues?
Thank you for this comment. The challenge is that patent laws vary between different countries so it is impossible to give one answer that applies everywhere.
There are three aspects to this question: the IP of the ASO sequence, the IP of the approach and the IP for the ASO chemistry.
To start with the last one, in the guideline we recommend using only the chemistry with a proven clinical track record. For CNS this would be MOE-PS, which is off patent, so that makes this aspect less relevant for now.
Whether there is ‘broad claim’ IP for the approach will of course rely on the approach that is taken (RNase H, splice modulation etc).
For the specific ASO sequence: how we foresee this in the Netherlands is that when we develop an ASO for a single patient or a very small group of patients, we make the ASO sequences that are effective publicly known as soon as possible. That way no one can file for IP because there is prior art. The aim is not to commercialize the ASOs after all, but to use them as personalized therapies. By publishing the sequences and rationale, it will then become impossible for companies to then file IP for this. This would work in the Netherlands. I do not know whether it would work in the same way in other countries.
IP and related issues probably merit from more discussion. Note that I think we all agree on how things should be – what we need to discuss is whether current regulations may impede the development of N=1+ ASOs and how to solve this.
We are planning a multistakeholder meeting (the one that was postponed from April 2020), where we can also discuss this in more detail.
Long-Cheng, thanks for this IP question, which will be of interest to many OTS members and others involved in N-of-1 therapeutics. IP questions can be complicated, so I turned to a friend and local biotech patent attorney, Amy Mandragouras, and her colleague, Maya Elbert, who have kindly provided the following response to your question:
From the US patent law perspective, pre-clinical and clinical studies to generate data for reasons related to FDA approval are exempt from infringement (under a Safe Harbor provision). In general, the standard for determining whether a study is “reasonably related” to FDA approval is quite liberal. For example, experiments with drug candidates to determine a lead candidate, including those for which FDA approval is not ultimately sought, fall under the Safe Harbor provision. In view of this, assuming an n-of-1 trial is performed for purposes of eventual FDA approval of an ASO, or one of the ASOs, made and tested by AMCs/investigators (or CRO) should, in general, be exempt from liability in the US under the Safe Harbor provision. That said, we have not specifically considered the n-of-1 trial format, and the likelihood that it would fall under the Safe Harbor provision (there may be circumstances under which a study may not be deemed “reasonably related” to FDA approval). It is important to be aware of patent rights that exists on the product being made and tested and its use, and the patent term. Especially considering that, once FDA approval is obtained and the drug product is commercialized, such patents may be enforced against entities making and commercializing the drug product.
Similar to Annemieke’s comment regarding the legal standard in Netherlands, in the US, if a particular ASO sequence and its efficacy for treatment of a certain disease are made publicly known, such art would make it difficult to obtain later-filed patents protecting the ASO or the already known use. However, new patents covering relevant use of the ASO may still be sought, for example, to a new ASO formulation, delivery vehicle, nucleotide modification, dosage, administration regime, combination treatment, or a new use, etc. for the relevant class of ASOs or the particular ASO of interest.
These are general comments on potential patent issues under US law. We have not considered any particular patent protection in the US on these technologies, or whether such technologies are off patent or covered by patents which will expire prior to FDA approval of an ASO.
Amy.Mandragouras@nelsonmullins.com
Maya.elbert@nelsonmullins.com
This document is very informative and helpful for us. Thanks for sharing.
By the way, I am wondering if I can get more detail info about the Appendix 1 -GMP guidelines for ASO production. For example, in the Appneidx 1, there are a couple of sections (e.g., 32S22, 32S23, 32S24, … 32S42 and 32S43) referred in the document but I was unable to find them in this document (or in other references).
I appreciate for your comments in advance. Thanks, Young
Dear Young Shin
Sorry for the late answer but I have been informed about your question just recently.
First, acknowledging the relevance of your comment, we will modify the document in order to make it more explicit to people who are not 100% CMC specialists.
All the 32Snn or 32Pnn references are references to the table of content of the FDA module 3 (Quality) in an IND submission package.
32S22 is for “Description of the Manufacturing process and process control
32S42 is for “Analytical procedures” in the 32S4 part entitled “Control of Drug Substance”
The complete ToC can be find on the FDA website at //www.fda.gov/media/83891/download [link tested on 01/18/2021 and OK]
I hope it helps